It heads northwest through a business district as a four-lane undivided highway to cross Sowashee Creek and have an interchange with Russell Drive/B Street before making a sharp right onto Front Street (Original US 45).

The highway now makes a sharp left turn at the southern end of unsigned MS 884 (OLD US 45) and heads north as a divided highway through neighborhoods and suburbs for several miles before leaving the city limits and entering the hilly woodlands of the North Central Hills.

MS 39 passes through the community of Lizelia, where it has an intersection with MS 854 (John C Stennis Drive; provides access to the community of Meridian Station and Naval Air Station Meridian) and narrows to two-lanes, before passing through the community of Daleville and crossing into Kemper County.

The highway makes a sharp left onto Church Street for a block before making a sharp right onto Main Avenue and passing straight through downtown (and directly beside the Kemper County Courthouse).

MS 39 leaves downtown and has a short concurrency with MS 16 before leaving De Kalb altogether and traveling through hilly remote woodlands for several miles, where it crosses the Sucarnoochee River before entering Noxubee County.